Methotrexate poses only a slight risk of pulmonary complications in rheumatoid arthritis patients, according to a meta-analysis of 22 double-blind, randomized trials comparing methotrexate to other drugs.
Physicians have worried for years that methotrexate might damage the already-frail lungs of RA patients, but the results suggest "the risk may be lower than previously believed," said the Irish investigators, led by Dr. Richard Conway, a senior research fellow in the department of rheumatology at Galway (Ireland) University Hospitals (Arthritis Rheum. 2013 Dec. 24 [doi: 10.1002/art.38322]).
Dr. Richard Conway
Previous reports estimated that the incidence of methotrexate-induced lung disease was as high as 7.6% in RA patients, but the team found a modest increase in the risk of overall respiratory adverse events (relative risk, 1.10; 95% confidence interval, 1.02-1.19) and respiratory infections (RR, 1.11; 95% CI, 1.02-1.21), and no increase in noninfectious respiratory events (RR, 1.02; 95% CI, 0.65-1.60) and pulmonary deaths (RR, 1.53; 95% CI, 0.46-5.01).
The meta-analysis pooled trial results from as far back as 1990. Overall, 4,544 patients were treated with methotrexate, and 4,040 with active comparators. The studies ranged from 6 to 24 months in duration.
The findings matter because "the suspicion of methotrexate-induced lung injury frequently leads to the cessation of methotrexate in patients who may otherwise be benefiting from the treatment. It is ... of vital importance not to implicate methotrexate as a causative agent in adverse events with insufficient evidence, as the drug may save the patient’s life," the investigators wrote.
"In our experience, many cases of lung disease initially attributed to methotrexate are due to other causative factors including, but not limited to, rheumatoid interstitial lung disease and opportunistic infections, with some experiencing worsening lung disease following cessation of their methotrexate," they noted.
However, the team found that methotrexate users had an increased risk of pneumonitis in the studies that specifically reported pneumonitis rates (RR, 7.81; 95% CI, 1.76-34.72); one case was fatal.
But the finding "must be interpreted with caution due to the reduced number of patients in each group." Also, none of the 13 trials published after 2001 reported pneumonitis. Perhaps methotrexate complications were less well understood in the 1990s, so earlier trials included patients at higher risk for pulmonary problems. Also, investigators may have been more likely to pin pulmonary issues on methotrexate, the authors said.
The mean age in the studies that reported pneumonitis was 54.3 years, and 28% of the subjects were men, whereas the mean age in studies that did not report pneumonitis was 50.7 years and 22% of the patients were men.
"Historically, intramuscular gold and sulfasalazine, and more recently disease-modifying antirheumatic drugs such as leflunomide have [also] been linked to the development of interstitial lung disease. In recent times, a possible link has emerged with the use of a number of the biologic agents, initially anti-TNF-alpha agents and more recently rituximab and tocilizumab," the investigators wrote. All of those agents were among the comparators in the pooled trials.
"Rather than each single drug causing interstitial lung disease ... it is perhaps more likely that if a link is present, it involves the modification of the underlying pulmonary disease process in rheumatoid arthritis by the implicated agents," they suggested.
Dr. Conway and his colleagues had no external funding for the study, but he and three of the other four investigators reported grants and payments from almost 20 companies, including Roche, UCB, and Merck.